Molecular biomedicine最新文献

High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements constitutes a distinct clinicopathological entity characterized by aggressive behavior, inherent resistance to conventional immunochemotherapy, and suboptimal clinical outcomes. Within our cohort, MYC/BCL2 rearrangements defined double-hit lymphoma (DHL), MYC/BCL6 as DHL-BCL6, and concurrent MYC/BCL2/BCL6 as triple-hit lymphoma (THL). Here, we delineated the clinical characteristics and genetic aberrations of 112 DHL/THL patients to investigate the factors influencing lymphoma relapse and optimize treatment strategies. Compared to 80 DHL-BCL6 patients, DHL/THL manifested distinct features, including an increased prevalence of the germinal center B-cell-like subtype and co-expression of MYC/BCL2, and demonstrated significant associations with abbreviated progression-free and overall survival. Univariate and multivariate analyses identified Ann Arbor stage and serum lactate dehydrogenase elevation as independent prognostic determinants. Therapeutic intensification employing R-DA-EDOCH was correlated with enhanced survival outcomes, while consolidative autologous stem cell transplantation significantly improved prognosis in patients who achieved remission after first-line immunochemotherapy. Regarding genetic aberrations, oncogenic mutations were detected in 102 evaluable patients. EZH2 mutation occurred more frequently in DHL/THL, while TNFRSF14 mutation exhibited greater prevalence in THL. The EZB genotype was predominantly observed in DHL/THL patients, and those with TP53 abnormalities exhibited a further diminished prognosis. In terms of the immune microenvironment, the depleted lymphoma microenvironment (LME-DP) subtype, characterized by diminished immune cell infiltration, demonstrated a propensity for increased frequency in DHL/THL patients. Collectively, these findings advance the comprehensive understanding of DHL/THL pathobiology, underscoring the imperative for novel targeted agents and therapeutic approaches.

Gastrointestinal (GI) cancers pose a significant global health burden, driven by complex molecular alterations and microenvironmental interactions. Advances in molecular pathogenesis have elucidated recurrent driver gene mutations, such as KRAS, TP53, and APC, alongside dysregulated signaling pathways including Wnt, RAS-MAPK, and PI3K-AKT, which collectively underpin tumor initiation and progression. Complementing genetic changes, epigenetic alterations-such as DNA hypermethylation, histone modifications, and regulatory non-coding RNAs-further contribute to malignant evolution by reshaping chromatin architecture and gene expression. These mechanisms not only promote uncontrolled proliferation but also reinforce therapeutic resistance by dynamically modifying the tumor microenvironment (TME). Molecular subtyping efforts, including The Cancer Genome Atlas (TCGA) classification for gastric cancer (GC) and the Consensus Molecular Subtypes (CMS) for colorectal cancer (CRC), have delineated disease heterogeneity, revealing distinct pathogenic pathways and enabling refined prognostic stratification. Such insights provide the biological rationale for diagnostic techniques and targeted interventions. For instance, anti-EGFR and anti-VEGF monoclonal antibodies disrupt oncogenic signaling and tumor angiogenesis, respectively, and have demonstrated substantial clinical efficacy in selected patient populations. In parallel, immunotherapy has emerged as a transformative modality in oncology. Immune checkpoint inhibitors targeting PD-1/PD-L1 and CTLA-4 reinvigorate antitumor immunity and have reshaped standard-of-care protocols for several GI malignancies. Beyond conventional immunotherapies, innovative strategies such as CAR-T cell therapy and neoantigen-based vaccines are being actively investigated. These approaches aim to overcome immune evasion mechanisms and enhance tumor-specific targeting, offering promise for patients with resistant or advanced disease. This review comprehensively analyzes the evolving molecular landscape of GI cancers and the corresponding development of targeted and immunotherapeutic agents. It highlights a balanced integration of mechanistic discovery and clinical translation, underscoring their synergistic roles in advancing precision oncology and improving survival outcomes.

Interferons (IFNs) are a family of cytokines that orchestrate a wide range of antiviral, immunoregulatory, and antitumor activities. This review provides a comprehensive overview of the molecular mechanisms underlying IFN signaling, including both canonical JAK (janus kinases)-STAT (signal transducers and activators of transcription) pathways and non-canonical branches such as MAPK (mitogen-activated protein kinase) and PI3K (phosphoinositide 3-kinase)-AKT (protein kinase B)-mTOR (mechanistic target of rapamycin). The intricate interplay between these signaling modules and transcriptional, epigenetic, and post-transcriptional regulators is essential for maintaining immune homeostasis and tailoring context-dependent immune responses. Under physiological conditions, IFNs are essential for host defense, driving antiviral gene expression, activating innate immune cells, and shaping adaptive immune responses, including T and B cells. Conversely, dysregulation of IFN signaling contributes to the development of autoimmune diseases, neuroinflammation, cardiovascular disorders, and cancer. Tumor cells can exploit IFN-induced suppressive molecules to evade immune attack. The currently emerging therapeutic strategies of IFN signaling have evolved into a dual strategy: replacement therapy in immunodeficient states, and pathway inhibition in autoimmune conditions. Additionally, IFN-based combination therapies with immune checkpoint blockade and radiotherapy have demonstrated synergistic potential but require precise control of dosing and timing to avoid immune exhaustion. Advances in single-cell transcriptomics, proteomics, and metabolomics are providing novel insights into IFN heterogeneity, enabling the development of personalized IFN-based treatments. This review highlights the clinical implications and emerging strategies to harness or restrain IFN signaling for therapeutic benefit.

The integration of single-cell sequencing and organoid technologies has been transformative for biomedical research, enabling investigations of organ development, disease mechanisms, and therapeutic innovation at even finer resolutions. Organoids serve as 3D in vitro models that replicate the structural and functional complexity of human tissues, while single-cell sequencing can resolve cellular heterogeneity, transcriptional dynamics, and lineage trajectories at high resolution. This review systematically explores the synergistic potential of these two technologies across multiple domains. First, it describes their application in studying the developmental mechanisms of organs including the brain, lungs, heart, liver, intestines, and kidneys, revealing key signaling pathways and cellular interaction networks. Then, it details their application in studying in vitro models of various diseases, including neurodegenerative disorders, genetic diseases, infectious diseases, metabolic syndrome, and tumors, advancing the in-depth analysis of pathological mechanisms. By leveraging patient-derived organoid biobanks, combining these two technologies can accelerate drug screening and precision, while utilizing transplantable tissue constructs to pioneer regenerative medicine strategies. This review also highlights the strengths of combining these two technologies in dynamically decoding cellular behavior and communication networks. By constructing physiologically relevant multifunctional research platforms, the integration of single-cell sequencing with organoid models will accelerate the elucidation of disease mechanisms and drive innovative breakthroughs in precision medicine and regenerative medicine. Looking ahead, the deep integration of single-cell sequencing with organoids, combined with cutting-edge technologies such as spatial transcriptomics and gene editing, will continue to propel life sciences toward a transformative leap from descriptive research to mechanism-driven, precision-oriented, and personalized approaches.

The gene encoding the RNA-binding motif protein 47 (RBM47) is highly expressed in epithelial cells and its down-regulation is characteristic for many types of cancer, among them colorectal cancer (CRC). However, the underlying mechanisms for this differential expression of RBM47 and its functional consequences during CRC progression have remained unknown. Here we found that RBM47 expression progressively decreases during CRC progression and is associated with poor prognosis and the metastatic CRC subtypes CMS4 and CRIS-B. In mice and humans RBM47 expression was highest in endoderm-derived tissues. The expression of forkhead box A1 (FOXA1), a transcription factor essential for the development of endoderm-derived epithelial tissues, showed a positive correlation with RBM47 expression in human tissues, as well as in primary CRCs and derived cell lines. Like RBM47, FOXA1 showed a down-regulation during CRC progression that is associated with poor prognosis and CMS4/CRIS-B. Ectopic FOXA1 induced RBM47 via directly binding to FOXA1 binding sites within the RBM47 promoter region. Up-regulation of RBM47 was necessary for FOXA1-mediated mesenchymal-to-epithelial transition (MET) and inhibition of CRC cell migration and invasion. RBM47 expression was silenced by CpG methylation in mesenchymal-like CRC cell lines. Moreover, epigenetic silencing of RBM47 in primary CRCs was associated with liver metastases. Therefore, the down-regulation of RBM47 is presumably initially mediated by loss of FOXA1 expression and subsequently fixed by CpG methylation of the RBM47 promoter. This down-regulation of RBM47 facilitates EMT and thereby promotes CRC metastasis. Finally, our results show that CpG hypermethylation of the RBM47 promoter represents a potential biomarker for metastatic CRC.

Epigenetic regulation is a fundamental mechanism controlling gene expression and cellular function, primarily mediated through reversible modifications such as DNA methylation, histone acetylation, and chromatin remodeling. Dysregulation of critical epigenetic enzymes, including histone deacetylases (HDACs), DNA methyltransferases (DNMTs), and bromodomain and extraterminal domain (BET) proteins, has been closely associated with tumor initiation, progression, metastasis, immune evasion, and resistance to conventional therapies. Targeting these epigenetic regulators with small-molecule inhibitors or degraders has emerged as a promising therapeutic strategy, capable of reprogramming aberrant transcriptional networks and reshaping the tumor microenvironment. Beyond direct cytotoxic effects, epigenetic drugs have demonstrated the ability to enhance antitumor immunity by restoring antigen presentation, promoting immunogenic cell death, modulating cytokine profiles, and reversing local immune suppression. Recent preclinical and clinical studies have highlighted the potential of combining epigenetic therapies with immune checkpoint inhibitors to achieve synergistic antitumor responses and overcome resistance mechanisms. This review provides a comprehensive summary of the mechanisms of action, pharmacological characteristics, and clinical applications of epigenetic drugs, with a focus on innovative combination strategies and ongoing translational advancements. We also discuss future directions, emphasizing the need to improve drug specificity, minimize off-target effects, integrate personalized immunotherapeutic approaches, and identify predictive biomarkers to optimize patient selection and clinical outcomes. Overall, epigenetic therapy represents a versatile and evolving avenue for precision oncology with broad implications for tumor control and immunomodulation.

Mesothelin (MSLN) is among the most studied cancer-related antigens, and it is extensively studied as a therapeutic target for the treatment of various malignancies, including pleural mesothelioma, pancreatic ductal adenocarcinoma, and ovarian cancer. However, despite the development of many MSLN-targeting strategies, such as antibody-drug conjugates (ADC), bispecific antibodies, and CAR-T cells, clinical responses have remained limited, underscoring the need for a deeper understanding of MSLN biology. Over the past decades, many studies have highlighted a link between MSLN and cancer progression and its association with specific features within the tumor microenvironment (TME). More recently, mechanistic evidence has emerged showing the involvement of MSLN in the establishment of key malignant features, such as the epithelial-to-mesenchymal transition (EMT) and matrix metalloproteinase 7-mediated remodeling of the extracellular matrix (ECM). Furthermore, these studies also show a direct role for MSLN in the immunosuppressive polarization of the TME through the interaction with CD206 macrophage receptors (leading to an M2-like polarization) and by promoting the transition of mesothelial cells into specific cancer-associated fibroblasts (CAFs). This review synthesizes current evidence on MSLN transcriptional regulation and its functional implications in invasion, metastasis, and immune evasion. We also summarize ongoing therapeutic strategies targeting MSLN and discuss how TME-driven resistance mechanisms are shaping the next generation of MSLN-directed therapies. By integrating molecular insights with translational perspectives, this work provides a comprehensive overview of MSLN biology and its emerging therapeutic relevance in cancer.

Neutrophil extracellular traps (NETs) are web-like structures composed of DNA, histones, and antimicrobial proteins that extend the defensive repertoire of neutrophils beyond classical phagocytosis and degranulation. Initially considered solely antimicrobial, NETs are now recognized as dynamic regulators of immunity, inflammation, and tissue remodeling. Their formation is orchestrated by the generation of reactive oxygen species, neutrophil elastase-mediated chromatin remodeling, and peptidyl arginine deiminase 4-driven histone citrullination. At the same time, clearance involves DNase activity and macrophage-mediated phagocytosis. In physiological contexts, NETs immobilize and kill pathogens, restrict biofilm formation, and coordinate immune cell crosstalk, thereby supporting host defense and repair. However, when NET formation or clearance becomes dysregulated, these structures drive a broad spectrum of pathologies. Aberrant NET activity has been implicated in infectious diseases (bacterial, viral, fungal), autoimmune disorders such as systemic lupus erythematosus, ANCA-associated vasculitis, rheumatoid arthritis, Gout, and psoriasis, cardiovascular disorders including atherosclerosis, thrombosis, acute coronary syndrome, Myocardial ischemia/reperfusion injury, hypertension, atrial fibrillation, heart failure, and viral myocarditis, as well as cancer progression, metastasis, and other inflammation-associated disorders such as asthma, Alzheimer's disease, diabetes, and pregnancy-related complications. Advances in imaging, proteomics, and single-cell sequencing have expanded our ability to characterize NETs across contexts, revealing stimulus- and disease-specific heterogeneity. At the translational levels, therapies that inhibit NETs formation, promote their degradation, or regulate their release, including PAD4 and elastase inhibitors, DNase-based approaches, and antibody strategies, are under active investigation. By integrating these advances, this review provides a framework for translating NET biology into clinically relevant applications.

Triple-negative breast cancer (TNBC) is characterized by complex genomic background and treatment resistance. We first defined "Titin (TTN) inactivation", a state of TTN expression deficiency or mutation, affecting tumor progression. However, how TTN inactivation regulates immune escape and affects therapeutic resistance remains unclear. Using whole-exome sequencing, single-cell transcriptome sequencing, and spatial transcriptome sequencing, we screened the clinical features of TNBC patients with TTN inactivation who accepted neoadjuvant therapy. Meanwhile, we used CRISPR-Cas9 technology to construct various mutant TNBC cell lines. Lentiviral vector carrying TTN and delta-like ligand 4 (DLL4) was validated in vivo to verify potential mechanism. Myeloid-derived suppressor cells (MDSCs) metabolic function was measured using glycolysis-related molecular experiments. Immunotherapeutic agents against TNBC with TTN inactivation were explored in the orthotopic MCT4^fl/fl genetically modified mouse model. DLL4-regulated ecological niche was established in TNBC with TTN inactivation. Mechanistically, TTN deficiency and mutation led to DLL4 secretion in TNBC. DLL4 enhanced MCT4-mediated glycolysis via MDSCs-derived NOTCH2 signaling pathway, driving the malignant function and lactate acid excretion of MDSCs. DLL4-derived MDSCs promoted stemness-mediated drug resistance by inducing histone lactate modification in TNBC, suppressing the anti-tumor activities of CD8⁺T cells. Blocking the DLL4-MCT4 axis stimulated anti-tumor immunity and synergized with anti-PD-1, improving response rates for first-line neoadjuvant therapy in TNBC. Our study revealed intrinsic mechanism by which TTN regulates the tumor immune microenvironment and provided a potential target for immunotherapy in TNBC with TTN inactivation.

Mitochondria play an essential role in regulating various physiological functions including bioenergetics, calcium homeostasis, redox signaling, and lipid metabolism and also are involved in the pathogenesis of cardiovascular diseases. However, the relationship between mitochondrial calcium homeostasis in vascular smooth muscle cells (VSMCs) and atherosclerosis remains poorly understood. Here, we demonstrate that cholesterol induces mitochondrial calcium overload and lipid accumulation in VSMCs, which is resulted from dysregulation of mitochondrial calcium uniporter (MCU), as evidenced by genetic and pharmacologic inhibition of MCU. Furthermore, MCU inhibitors alleviate Western diet-induced atherosclerosis in ApoE-/- mice. Mechanistically, high-fat and high-cholesterol diets induce the contact between mitochondria and the endoplasmic reticulum (ER) in VSMCs as indicated by transmission electron microscopy, proximity ligation assay and immunofluorescence staining, which increases the formation of mitochondria-associated membranes (MAMs), leading to Ca2 + release from the ER into the mitochondria and thus elevating Ca2 + in the mitochondria. Using mitochondrial calcium uptake 1 (MICU1) mutant and Ca2 + detection assay, we confirmed that this increased Ca2 + binds to MICU1, a blocker of MCU, to impair its ability to block MCU, thus enabling the MCU to remain open and resulting in mitochondrial calcium overload. Further, mitochondrial calcium overload dysregulates fatty acid β-oxidation by modulating medium-chain acyl-CoA dehydrogenase (ACADM), thereby leading to lipid deposition. The inhibition of MCU alleviates the pathological changes elecited by cholesterol. Our findings unveil the previously unrecognized role of MAM-MICU1-MCU axis in cholesterol-induced mitochondrial calcium overload and atherosclerosis, indicating that MCU represents a promising therapeutic target for the treatment of atherosclerosis.